Abstract

Aims/hypothesis

Methods

C57BL/6J mice were fed with a low-fat diet (10% of energy as fat), a high-fat diet (HFD) (45% of energy as fat) or a HFD with oltipraz for 28 weeks. The effects of oltipraz on body weight, fat content, glucose disposal, insulin signalling, metabolic profiles and endogenous NRF2 functional status in the three groups of mice were investigated.

Results

Oltipraz prevented or significantly attenuated the effect of HFD on glucose disposal, body weight and fat gain. Impairment of protein kinase B/Akt phosphorylation in this HFD-fed mouse model in response to intraperitoneal insulin injection was observed in adipose tissue, but not in the muscles, accompanied by inhibition of AMP-activated protein kinase signalling and activation of p70S6 kinase, as well as reduced GLUT4 content. These defects were attenuated by oltipraz administration. Nuclear content of NRF2 in adipose tissue was reduced by HFD feeding, associated with increased Keap1mRNA expression and reduced production of haem oxygenase-1 and superoxide dismutase, increased protein oxidation, decreased plasma reduced:oxidised glutathione ratio and the appearance of macrophage marker F4/80. These defects were also restored by oltipraz. Finally, oltipraz attenuated HFD-induced inducible nitric oxide synthase overproduction.

Conclusions/interpretation

Impairment of the endogenous redox system is important in the development of obesity and insulin resistance in chronic HFD feeding. NRF2 activation represents a potential novel approach in the treatment and prevention of obesity and diabetes.

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Liver weight and lipid content. a The weight of the liver and (b) the amount of triacylglycerol (TG) in liver from mice on LFD, HFD and HFD + oltipraz (OPZ) diets for 28 weeks was measured after mice were killed (n = 8 for each group). c MRI assessment of intra-hepatic lipid content (n = 4). d Representative MRI spectra, including in-phase water resonance and inlay of in-phase fat resonance for each experimental group. au, arbitrary units; ppm, parts per million (PDF 41 kb)

Lipid content in the gastrocnemius muscle. a The amount of triacylglycerol (TG) in the gastrocnemius muscle from mice on LFD, HFD and HFD + oltipraz (OPZ) diets for 28 weeks was measured after mice were killed (n = 8 for each group). b MRI assessment of lipid content in the gastrocnemius muscle of the three groups of mice after 26 weeks of diet (n = 4). c Representative MRI spectra, including in-phase water resonance and inlay of in-phase fat resonance for each experimental group. au, arbitrary units; ppm, parts per million (PDF 21.7 kb)